Tetrahydro(1H)pyrazino(1,2-A)azaquinoxalin-5(6H)-ones and derivatives thereof

ABSTRACT

Compounds of the formula ##STR1## wherein: R is hydrogen, chlorine, or fluorine; and 
     R 1  is hydrogen, methyl, ethyl, propyl, or isopropyl; 
     or a non-toxic acid addition salt thereof; exert an anti-hypertensive effect.

This is a division of application Ser. No. 821,381 filed Aug. 3, 1977now U.S. Pat. No. 4,138,564 issued Feb. 6, 1979.

The present invention relates to substituted7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-ones,7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[4,3-e]pyrazin-6(6aH)-ones,and2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]pyrido[2,3-e]-pyrazin-5(6aH)-ones,which compounds have pharmacological activity. Also contemplated by thisinvention are intermediates used in the synthesis of said compounds,pharmaceutical compositions containing said compounds, and methods ofusing said compounds.

The invention sought to be patented comprises chemical compounds of theformula: ##STR2## wherein: R is hydrogen, chlorine, or fluorine; and

R¹ is hydrogen, methyl, ethyl, propyl, or isopropyl; or a non-toxic acidaddition salt thereof.

The compounds of Formula Ia, Ib, or Ic, wherein R and R¹ have themeanings above-defined, and the non-toxic acid addition salts thereof,exert a hypotensive effect in hypertensive warm-blooded animals, asevidenced by pharmacological evaluation in standard test procedures.

Preferred compounds of Formula Ia, Ib, or Ic are those in which R andR¹, are each hydrogen. When R is a group other than hydrogen, fluorineis preferred.

Also within the scope of this invention are the intermediates employedin the synthesis of the compounds of Formula Ia, Ib, or Ic. Suchintermediates are:

(a) compounds of the formula: ##STR3## wherein: Y is methyl, ethyl,propyl, isopropyl, or a protecting group for a secondary amine; and

R is hydrogen, chlorine, or fluorine;

or an N-oxide or a salt thereof; and

(b) compounds of the formula: ##STR4## wherein: Y¹ is a protecting groupfor a secondary amine; and

R is hydrogen, chlorine, or fluorine.

As used herein the term "protecting group for a secondary amine" ismeant a group which will prevent undesirable side reactions at thesecondary amine nitrogen during reactions leading to the final products,but will be easily removed by chemical means, when desired, to obtainthe final products. Such protecting groups are conventional in the artof chemistry. Examples are: carbobenzoxy, benzhydryl, benzyl,trifluoroacetyl, t-butyloxycarbonyl, or tosyl. The carbobenzoxy group ispreferred.

The general method of synthesis of the compounds of Formula Ia, Ib, orIc is illustrated schematically in FIG. I of the annexed Drawing whichdepicts the preparation of 7, 8, 9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one and themethyl substituted derivative thereof.

The method depicted in FIG. I employs intermediates in which theprotecting group (Y or Y¹) for the secondary amine nitrogen isillustrated by the carbobenzoxy group (represented in FIG. I by thesymbol CBZ) having the structure: ##STR5## The symbol X in Formula IIIrepresents a chlorine, fluorine, or bromine atom.

Referring now to FIG. I, wherein the compounds are assigned Romannumerals for identification, in Process A,4-carbobenzoxypiperazine-2-carboxylic acid (II) is condensed with a2-halo-3-nitropyridine (III), to afford4-carbobenzoxy-1-(3-nitro-2-pyridinyl)piperazine-2-carboxylic acid (IV).The reaction is carried out in an inert organic solvent, such asdimethylsulfoxide, dimethylformamide, or a water-(lower)alkanolsolution, in the presence of a base, such as a teriary-alkyl amine (e.g.triethylamine) or an alkali metal carbonate or bicarbonate at atemperature from about 20° to about 100° C., preferably 60° C.

The intermediate IV is cyclized to8-carbobenzoxy-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-oneby a two-step process involving reduction of the nitro group to theamino group followed by cyclization. The reduction step is preferablyperformed by treating the nitro acid (IV) with a reducing agent, such asiron-acetic acid or sodium dithionite at a pH of 8-10. Other standardreagents capable of reducing an aromatic nitro group will be obvious tothose skilled in the art. The amino acid thus produced is cyclized byadjusting the pH of the solution to about 7.5 or less (preferably a pHof about 3).

The 3-carbobenzoxy protecting group is removed from8-carbobenzoxy-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]-pyrazin-6(6aH)-one(V) by catalytic hydrogenation (Process C) to afford 7, 8, 9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]-pyrazin-6(6aH)-one (VI).The hydrogenation is carried out in an inert solvent, such as ethanol,in the presence of a catalyst, such as a noble metal (e.g. Raney nickelor palladium on carbon), at a pressure of from about 1 atm. to about 3atm., preferably about 3 atom. If desired, the hydrogenation may beperformed in the presence of an acid, such as hydrogen chloride whichprovides the product as the acid addition salt.

Catalytic hydrogenation (e.g. with Raney nickel) of the intermediate(IV) in the presence of an acid effects reduction, cyclization, andremoval of the carbobenzoxy group and yields the product VI directly(Process I).

When it is desired to prepare the product containing a substituent atthe 8-position,7,8,9,10-tetrahydro-5H-pyrazino-[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(VI) is treated with a suitable alkylating agent (Process D), forexample, an alkyl halide. The reaction is performed in an inert solvent,such as ethanol, preferably in the presence of a weak base, such aspotassium carbonate. Other alkylating agents, such as the tosylatederivatives, will be apparent to those skilled in the art.

While the above method of synthesis has been described by reference toFIG. I which illustrates the preparation of7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (acompound of Formula Ia), it will be apparent to those skilled in the artof chemistry that the compounds of Formula Ib and Ic may be prepared bythis method or by modifications of this method which would be obvious tothose skilled in the art. Thus, compounds of Formula Ib and Ic may beprepared by employing an appropriate nitrohalopyridine in Process A andusing the intermediates formed therefrom in the subsequent processes.For example;7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[4,3-e]-pyrazin-6(6aH)-onecan be prepared from a 3-halo-4-nitropyridine while2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]pyrido[2,3-e]pyrazin6(6aH)-one canbe prepared from a 2-nitro-3-halopyridine.

The nitrohalopyridines employed as starting materials in the processdescribed above are either known compounds or may be prepared from knowncompounds by methods which will be apparent to one skilled in the art ofchemistry. The term "nitrohalopyridine" means a nitropyridine containinga fluorine, chlorine, or bromine atom in the appropriate position orthoto the nitro group. The nitrofluoropyridines are preferred startingmaterials since the fluorine atom is more easily replaced than chlorineor bromine. In some instances, it may be more convenient to use theN-oxide of the nitrohalopyridine, and for synthetic purposes suchN-oxides are equivalent to the free base.

It will also be apparent that the nitrohalopyridine starting materialsemployed for preparing the compounds of Formula Ia can be furthersubstituted with a chlorine or fluorine atom at a position ortho to thepyrido nitrogen, and such starting materials will afford the compoundsof Formula Ia when R is chlorine or fluorine.

4-Carbobenzoxypiperazine-2-carboxylic acid (II) employed as a startingmaterial in Process A is prepared from piperazine-2-carboxylic acid inthree steps: (a) treating said acid, as the dihydrochloride, with cupriccarbonate in water to form the cupric ion chelate; (b) treating thechelate with benzylchloroformate in acetone-water to introduce thecarbobenzoxy group; and (c) treating the3-carbobenzoxypiperazine-2-carboxylic acid, copper chelate withhydrochloric acid and hydrogen sulfide to destroy the chelate. Theproduct is isolated as the hydrochloride salt. Other protectedpiperazine-2-carboxylic acids may be similarly prepared by treating thepiperazine-2-carboxylic acid cupric ion chelate with a suitable blockingreagent to introduce the blocking group at the 4-position and thendestroying the chelate.

In the method of synthesis depicted in FIG. I, the carbobenzoxy group isemployed as a blocking group to protect the reactive nitrogen of thepiperazine ring of the intermediates. It will be obvious to thoseskilled in the art that any conventional blocking group useful forprotecting a secondary amino group may be employed, for example; thebenzhydryl, benzyl, trifluoroacetyl, t-butyloxycarbonyl, or tosyl group.Methods for removing a particular protecting group will be obvious toone skilled in the art of organic chemistry. For example a benzyl-typeblocking group (e.g. a benzhydryl, benzyl, or carbobenzoxy group) can beremoved by catalytic hydrogenation (hydrogenolysis). Hence,catalytically reducing an intermediate of Formula Ic containing thebenzhydryl, benzyl, or carbobenzoxy group in the presence of an acideffects reduction, cyclization, and removal of the blocking group andprovides a convenient method for preparing the compounds of Formula Iawherein R and R¹ are hydrogen.

Certain blocking groups (e.g. carbobenzoxy, t-butyloxycarbonyl,trifluoroacetyl, or tosyl) can be removed by acid hydrolysis such as bytreatment with hydrochloric acid.

The compounds of Formula Ia, Ib, or Ic, wherein R is methyl, ethyl,propyl, or isopropyl are conveniently prepared by an alternate processin which a 4-(lower)alkylpiperazine-2-carboxylic acid is employed inplace of 4-carbobenzoxypiperazine-2-carboxylic acid (II) in Process Adescribed above. Reduction of the nitro group of the product thus formedfollowed by cyclization (as in Process B, described above) directlygives the desired product without the need for blocking and deblockingthe piperazine nitrogen.

Since the compounds of Formula Ia, Ib, or Ic possess an asymmetriccarbon atom, optical enantiomorphs are possible, and the compounds ofthe invention may be in the form of the pure enantiomorph or mixturesthereof, such as the racemates.

The compounds of Formula Ia, Ib, or Ic may be obtained in the form ofthe pure enantiomorph either by resolving a desired racemic product orby resolving a racemic starting material or intermediate at anyconvenient stage of the synthesis. Methods of carrying out theresolution are well known in the art of chemistry. For example, thedesired racemate may be treated with an optically active carboxylic acidand the optically active addition salts may be separated by standardtechniques.

The compounds of Formula Ia, Ib, or Ic as obtained in the processesdepicted in FIG. I, and the appropriate intermediates thereto, may beisolated and purified in a conventional manner. It is furthermoreappreciated that in the various processes hereinbefore described,factors such as solvents or temperatures are not critical and theselection of a temperature or solvent for a particular process will beapparent to one skilled in the art.

The compounds of Formula Ia, Ib, or Ic may exist either in the form ofthe free base or the acid addition salt. Methods for converting one suchform to another will be obvious to one skilled in the art of chemistry.

The amino acids, 4-(substituted)piperazine-2-carboxylic acid and the4-(substituted)-1-(nitropyridinyl)piperazine-2-carboxylic acids,employed as intermediates for preparing the compounds of Formula Ia, Ib,or Ic may exist either in the acid, base, or zwitterion form, andmethods for converting one such form to another will be apparent tothose skilled in the art.

For pharmacological use, the compounds of Formula Ia, Ib, or Ic may beadministered in the form of an acid addition salt of a non-toxic organicor inorganic acid. The salts may be prepared by methods well known inthe art. Appropriate salts are those formed from the following acids:hydrochloric, hydrobromic, sulfonic, sulfuric, phosporic, nitric,maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic,acetic, propionic, tartaric, citric, lactic, malic, mandelic, cinnamic,palmitic, itaconic, and benzenesulfonic.

When employed to relieve hypertension, the effective dosage of thecompounds of Formula Ia, Ib, or Ic will vary according to the particularcompound being employed, the severity and nature of the hypertension,and the particular subject being treated. In general, with largewarm-blooded animals (about 70 kg. body weight) effective results can beachieved by the oral route at a dosage level of from 25 mg. to about 2g. given as needed, for example every four to six hours. A dose of about25 mg. to about 500 mg. is preferred. Therapy should be initiated atlower dosages, the dosage thereafter being increased until the desiredhypotensive effect is obtained.

When employed as hypotensive agents, the active substances of FormulaIa, Ib, or Ic may be administered alone or in combination withpharmaceutically acceptable carriers, the proportion and nature of whichare determined by the solubility and chemical properties of the compoundselected, the chosen route of administration, and standardpharmaceutical practice. For example, the compounds of Formula Ia, Ib,or Ic may be administered orally in solid dosage forms, e.g. capsules,tablets, or powders, or in liquid forms, e.g. solutions or suspensions.The compounds may also be injected parenterally in the form of sterilesolutions or suspensions. Solid oral forms may contain conventionalexcipients, for instance: lactose, succrose, magnesium stearate, resins,and like materials. Liquid oral forms may contain various flavoring,coloring, preserving, stabilizing, solublizing or suspending agents.Parenteral preparations are sterile aqueous or non-aqueous solutions orsuspensions which may contain various preserving, stabilizing,buffering, solubilizing, or suspending agents. If desired, additives,such as saline or glucose may be added to make the solutions isotonic.

The following examples are illustrative of the processes of theinvention. All temperatures are in centigrade.

EXAMPLE 1 1-(3-Nitro-2-pyridinyl)-4-carbobenzoxypiperazine-2-carboxylicacid

A solution of 6.0 g. of 4-carbobenzoxypiperazine-2-carboxylic acidhydrochloride, 3.3 g. of 2-chloro-3-nitropyridine and 15 ml. of triethylamine in 100 ml. of dimethyl sulfoxide is heated at 60° with stirringfor 18 hours. The mixture is diluted with 400 ml. of water, acidified topH 3 with concentrated hydrochloric acid, and extracted repeatedly withether. The combined ether extracts are dried (MgSO₄) and concentrated.The residue is crystallized from ethyl acetate/heptane to give 6.3 g. ofthe title product, m.p. 145°-147°.

Analysis for: C₁₈ H₁₈ N₄ O₆ ; Calculated: C, 55.95; H, 4.70; N, 14.50;Found: C, 55.62; H, 4.68; N, 14.67.

EXAMPLE 2 1-(4-Nitro-3-pyridinyl,N-oxide)-4-carbobenzoxypiperazine-2-carboxylic acid

A mixture of 3.48 g. of 3-fluoro-4-nitropyridine-N-oxide, 6.6 g. of4-carbobenzoxypiperazine-2-carboxylic acid hydrochloride, 15 ml. oftriethylamine, and 100 ml. of methanol is stirred at room temperaturefor 18 hours. The solution is concentrated and the residue is dissolvedin aqueous potassium bicarbonate solution. The pH is adjusted to 3 withaqueous hydrogen chloride then treated with methylene chloride and theresultant mixture is filtered to give 4.6 g. of the title product, m.p.145° dec. Thin layer chromatographic analysis of this material shows onesingle spot.

Analysis for: C₁₈ N₁₈ N₄ O₇.1/2H₂ O; Calculated: C, 52.55; H, 4.65; N,13.62; Found: C, 52.39; H, 4.48; N, 13.50.

EXAMPLE 3 1-(2-Nitro-3-pyridinyl)-4-carbobenzoxypiperazine-2-carboxylicacid

A mixture of 2.8 g. of 2-nitro-3-fluoropyridine, 5.0 g. of4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, 25 ml. oftriethylamine, and 90 ml. of dimethyl sulfoxide is heated at 55° withstirring for 11/2 hours, then allowed to stand at room temperatureovernight. A similar workup to that described in Example 1 gives 4.5 g.of the title product as a viscous orange glass. Thin layerchromatographic analysis of this material shows one single spot.

EXAMPLE 41-(6-Fluoro-3-nitro-2-pyridinyl)-4-carbobenzoxypiperazine-2-carboxylicacid

In a similar procedure to that described in Example 1, from 6.0 g. of2,6-difluoro-3-nitropyridine, 9.0 g. of4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, 20 ml. oftriethylamine and 150 ml. of dimethyl sulfoxide, there is obtained 14 g.of the title product as a viscous orange glass. Thin layerchromatographic analysis of this material shows essentially one spot.

EXAMPLE 58-Carbobenzoxy-7,8,9,10-tetrahydro5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazino-6(6aH)-one

A solution of 1.95 g. of1-(3-nitro-2-pyridinyl)-4-carbobenzoxypiperazine-2-carboxylic acid in250 ml. of water is adjusted to pH 9-10 with aqueous sodium hydroxide.To this solution, with stirring, is added 3.5 g. of sodium dithionite insmall portions. The pH is maintained between 8 and 10 by addition ofsmall portions of aqueous sodium hydroxide while the dithionite is beingadded. After the addition of dithionite the pH of the solution isbrought to 3 with concentrated hydrochloric acid, then is brought backto pH 10 with aqueous sodium hydroxide. The mixture is extracted withmethylene chloride, dried (MgSO₄), and concentrated to give 0.5 g. ofthe title product as a tan solid. After recrystallization from ethanol,m.p. 188°-189°.

Analysis for: C₁₈ H₁₈ N₄ O₃.1/2H₂ O; Calculated: C, 62.23; H, 5.51; N,16.13; Found: C, 62.58; H, 5.38; N, 16.25.

EXAMPLE 68-Carbobenzoxy-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[4,3-e]pyrazin-6(6aH)-one

To a solution of 2.0 g. of 1-(4-nitro-3-pyridinyl,N-oxide)-4-carbobenzoxypiperazine-2-carboxylic acid, 25 ml. of aceticacid is added, while stirring, 1.5 g. of iron powder. The mixture iswarmed to 55° for 1/2 hour then concentrated. The residue is treatedwith 10% hydrochloric acid and filtered to give 1.35 g. of the hydrogenchloride salt of the title compound with m.p. 234°-238°.Recrystallization from ethanol-water gives the the title product, m.p.255°-256° dec.

Analysis for: C₁₈ H₁₈ N₄ O₃.HCl.1/4H₂ O; Calculated: C, 56.99; H, 5.18;N, 14.77; Found: C, 56.81; H, 5.10; N, 14.50.

EXAMPLE 73-Carbobenzoxy-2,3,4,4a-tetrahydro1H-pyrazino[1,2-a]pyrido[2,3-a]pyrazin-5(6H)-one

To a solution of 4.5 g. of1-(2-nitro-3-pyridinyl)-4-carbobenzoxypiperazine-2-carboxylic acid in 75ml. of acetic acid is added, while stirring, 3.0 g. of iron powder. Themixture is heated to 60° for a few minutes then filtered andconcentrated. Water is added to the residue and the mixture is extractedwith methylene chloride, dried (MgSO₄) and concentrated to give 4.5 g.of the title product as a viscous glass. Crystallization from ethanol(Norit) gives 1.8 g., m.p. 190°-192°.

Analysis for: C₁₈ H₁₈ N₄ O₃ ; Calculated: C, 63.89; H, 5.36; N, 16.56;Found: C, 63.64; H, 5.42; N, 16.35.

EXAMPLE 88-Carbobenzoxy-2-fluoro-7,8,9,10-tetrahydro5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

To a solution of 14.0 g. of1-(6-fluoro-3-nitro-2-pyridinyl)-4-carbobenzoxypiperazine-2-carboxylicacid in 300 ml. of acetic acid is added, while stirring, 7.0 g. of ironpowder. The mixture is warmed to 55° for 3 hours then concentrated. Theresidue is treated with water and extracted with methylene chloride,dried (MgSO₄) and concentrated. The residue is placed on a dry column ofalumina and eluted with chloroform. The product band in the column iscut out and the product is washed from the alumina with methanol.Concentration of the methanol wash gives 5.0 g. of the lightgreen-colored title product. Recrystallization from ethanol gives 2.2 g.of pure product, m.p. 210°-214°.

EXAMPLE 97,8,9,10-Tetrahydro-5H-pyrazino-[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

A mixture of 1.5 g. of8-carbobenzoxy-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one,1 g. of 10% palladium on carbon, and 150 ml. of ethanol is hydrogenatedat 45 psi for 2 hours. The catalyst is filtered and the filtrate isconcentrated. The residue is dissolved in a small amount of ethanol andethanolic hydrogen chloride is added. Filtration of the precipitatedsalt gives 0.72 g. of the title product, m.p. 270° dec.Recrystallization from ethanol-water gives 0.60 g., m.p. 278°-279°.

Analysis for: C₁₀ H₁₂ N₄ O.HCl.H₂ O; Calculated: C, 46.42; H, 5.84; N,21.65; Found: C, 46.32; H, 5.12; N, 21.42.

EXAMPLE 107,8,9,10-Tetrahydro-5H-pyrazino-[1,2-a]pyrido[4,3-e]pyrazin-6(6aH)-one

In a similar procedure to that described in Example 9, from 1.1 g. of8-carbobenzoxy-7,8,9,10-tetrahydro-5H-pyrazino-[1,2-a]pyrido[4,3-e]pyrazin-6(6aH)-one,there is obtained 0.45 g. of the title product as the hydrochloridesalt, m.p. 303°-306°.

Analysis for: C₁₀ H₁₂ N₄ O.2HCl.1/4H₂ O; Calculated: C, 42.64; H, 5.19;N, 19.89; Found: C, 42.45; H, 5.14; N, 19.87.

EXAMPLE 112,3,4,4a-Tetrahydro-5H-pyrazino[1,2-a]pyrido[2,3-e]pyrazin-5(6H)-one

In a similar procedure to that described in Example 9, from 1.75 g. of3-carbobenzoxy-2,3,4,4a-tetrahydro-5H-pyrazino-[1,2-a]pyrdio[2,3-e]pyrazin-5(6H)-one,there is obtained 0.55 g. of the title product as the hydrochloridesalt, m.p. 315°-319°.

Analysis for: C₁₀ H₁₂ N₄ O.HCl.1/4H₂ O; Calculated: C, 48.98; H, 5.37;N, 22.85; Found: C, 48.90; H, 5.25; N, 22.79.

EXAMPLE 122-Fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one

In a similar procedure to that described in Example 9, from 2.0 g. of8-carbobenzoxy-2-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one,there is obtained 0.85 g. of the title product as the hydrochloridesalt, m.p. 305°-308°.

Analysis for: C₁₀ H₁₁ H₄ OF.HCl.1/4H₂ O; Calculated: C, 45.63; H, 4.79,N, 21.29; Found: C, 45.81; H, 4.75; N, 21.13.

EXAMPLE 13

The antihypertensive effect of a compound of Formula Ia, Ib, or Ic isellicited and demonstrated by administering the compound to ahypertensive rat and measuring the change in systolic blood pressure 2and 4 hours after administration. The rats used are either spontaneouslyhypertensive or are rendered hypertensive by applying a figure-of-eightligature around one kidney and contralateral nephrectomy. Malespontaneously hypertensive rats derived from the Okamoto-Aoki strainwere purchased from commercial breeders. In the renal hypertensive rats,blood pressure tends to stabilize at a hypertensive level afterapproximately six weeks. A group of at least 4 rats is given thecompound by the oral (P.O.) route. Systolic blood pressure, as measuredby an indirect technique using the Decker Caudal Plethysmorgraph, ismeasured prior to administration of the compound and at 2 and 4 hoursthereafter. This schedule may vary depending upon the behavior of thecompound. A control group of rats, given either a placebo or a standardantihypertensive agent is run with each group of treated rats.

The hypotensive activity of the compound is rated as follows:

    ______________________________________                                                           Systolic Decrease                                          Activity           in Blood Pressure                                          ______________________________________                                        Slight             25-35 mm Hg                                                Moderate           35-50                                                      Marked             over 50                                                    ______________________________________                                    

When tested as described above, the compounds of Formula Ia, Ib, or Icgave the following results:

    ______________________________________                                        Compound              Activity (P.O.)                                         ______________________________________                                        7,8,9,10-tetrahydro-5H                                                                              Moderate at                                             pyrazino[1,2-a]pyrido[3,2-e]-                                                                       2.5 mg/kg                                               pyrazin-6(6aH)-one                                                            7,8,9,10-tetrahydro-5H-                                                                             Slight at                                               pyrazino[1,2-a]pyrido[4,3-e]-                                                                       20 mg/kg                                                pyrazin-6(6aH)-one                                                            2,3,4,4a-tetrahydro-1H-                                                                             Marked at                                               pyrazino[1,2-a]pyrido[2,3-e]-                                                                       25 mg/kg                                                pyrazin-5(6H)-one                                                             2-fluoro-7,8,9,10-tetrahydro-                                                                       Marked at                                               5H-pyrazino[1,2-a]pyrido-                                                                           20 mg/kg                                                [3,2-e]pyrazin-6(6aH)-one                                                     ______________________________________                                    

What is claimed is:
 1. A compound of the formula: ##STR6## wherein R' ishydrogen, methyl, ethyl, propyl, or isopropyl; or a non-toxicpharmaceutically acceptable acid addition salt thereof.
 2. The compoundas defined in claim 1 which is2,3,4,4a-tetrahydro-5H-pyrazino[1,2-a]pyrido[2,3-e]pyrazin-5(6H)-one. 3.A compound of the formula: ##STR7## wherein Y¹ is carbobenzoxy,benzhydryl, benzyl, trifluoroacetyl, t-butyloxy carbonyl, or tosyl. 4.The compound as defined in claim 3 which is3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]pyrido[2,3-a]-pyrazin-5(6H)-one.